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Information about the main author:
25. Kamishov Sergey Viktorovich
26. MD, PhD, chemotherapeutist of chemotherapy department
27. Senior researcher
28. ID: ORCID 0000-0002-1581-6032
29. Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
30. 100174, Uzbekistan, Tashkent, 383 Farabiy st.
31. +998 90 978 65 38
32. E-mail: sergei_kamyshov@mail.ru
THE DEGREE OF IMMUNOLOGICAL DISORDERS AND THEIR DYNAMICS ON THE BACKGROUND OF IMMUNOTHERAPY IN PATIENTS WITH _OVARIAN CANCER_
Kamishov Sergey Viktorovich
MD, PhD, senior researcher, chemotherapy Department
Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry
of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
АННОТАЦИЯ
Цель исследования: изучение степени иммунологических нарушений у больных РЯ, в частности, основных параметров врожденного и адаптивного иммунитета, а также определенного спектра цитокинов до применения различных видов иммунотерапии и на фоне применения ЭИФТ и ПФ. Методы: В обследование были включены 176 больных РЯ Т2-3М0-1Ыо стадий (II-III клинические стадии). В соответствии с поставленными задачами исследования, больные РЯ были разделены на группы с целью проведения сравнительной характеристики иммунологических результатов в зависимости от используемого метода иммунотерапии, вошедшего в состав комплексного лечения. Результаты: Выявлена активация CD95+ на Т-лимфоцитах, что подтверждает наличие Т-клеточного иммунодефицита за счет апоптоза Т-лимфоцитов. Включение в комплекс сопроводительного лечения ЭИФТ и ЭИФТ+ПФ, является одним из путей уменьшения эндогенной интоксикации при проведении противоопухолевой лекарственной терапии. Разработанная методика ЭИФТ имеет большие перспективы в онкологической практике в связи с возможностью снимать последствия раковой и химиолучевой интоксикации, а также активировать систему противоопухолевой защиты организма. Выводы: применение ЭИФТ и ЭИФТ+ПФ с последующей неоадъювантной ПХТ у больных РЯ с клинико-лабораторными признаками эндогенной интоксикации является оправданным и эффективным методом, так как приводит к нормализации показателей основных сывороточных ци-токинов иммунной системы, позволяет улучшить непосредственные результаты лечения, приводит к уменьшению клинических проявлений заболевания, улучшает качество жизни больных, позволяет переводить больных из неоперабельного состояния в операбельное.
Ключевые слова: рак яичников, иммунотерапия, экстракорпоральная иммунофармакотерапия, иммунитет, интерлейкины, полихимиотерапия
ABSTRACT
The aim of the study was to study the degree of immunological disorders in patients with ovarian cancer, in particular, the basic parameters of congenital and adaptive immunity, as well as a certain spectrum of cytokines before the application of various types of immunotherapy and against the background of the use of EIPHT and PPh. Methods: 176 patients with T2-3N0-1M0 stages (II-III clinical stages) were included in the survey. In accordance with the objectives of the study, patients with OC were divided into groups in order to perform a comparative analysis of the immunological results, depending on the immunotherapy method used, which was included in the complex treatment. Results: activation of CD95 + on T-lymphocytes was confirmed, which confirms the presence
of T-cell immunodeficiency due to apoptosis of T-lymphocytes. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. The developed EIPHT technique has great prospects in oncological practice in connection with the possibility to remove the consequences of cancer and chemoradiation intoxication, and also to activate the system of antitumor protection of the organism. Conclusions: the use of EIPHT and EIPHT + PPh with subsequent neoad-juvant PCT in patients with ovarian cancer with clinico-laboratory signs of endogenous intoxication is justified and effective, since it leads to normalization of the indices of the main serum cytokines of the immune system, allows to improve immediate results of treatment, leads to a reduction in clinical manifestations of the disease, improves the quality of life of patients, allows you to transfer patients from an inoperable state to an operable state.
Key words: ovarian cancer, immunotherapy, extracorporeal immunopharmacotherapy, immunity, interleu-kins, polychemotherapy.
Topicality. It is known that imbalance in the immunity system is considered as an important mechanism for the development of many immunopathological processes, including ovarian cancer [1, -P.433; 2,-P. 169; 7,P. 3399]. All modern methods of treatment of ovarian cancer are known to initiate immunosuppres-sion mainly on the cellular type, which is extremely dangerous, since the tumor in turn also uses suppression mechanisms to reduce the body's response to its presence. In this regard, the improvement of methods of diagnosis and treatment of ovarian cancer remains one of the urgent problems of oncology, which is caused by unsatisfactory results of therapy of this disease. Ovarian cancer (OC) occupies a stable 3 rd place in the structure of oncogenital pathology. Mortality from OC exceeds mortality from cervical cancer and uterus body combined, despite the advances in diagnosis and treatment. The asymptomatic course of the disease in the early stages, leading to late treatment to the doctor, and, consequently, to detectability with already widespread stages of the disease (up to 70%) leads to a high mortality of patients [5,8]. The course of the tumor process, in particular, with OC, is accompanied by the formation of endotoxicosis and secondary immunological failure. Moreover, endotoxicosis is a complex, multicomponent process, which is caused by the accumulation of endotoxic substances in tissues and biological fluids in conditions of a decrease in the physiological processes of detoxification. Carrying out chemotherapy contributes to the further growth of endogenous intoxication, the suppression of the body's immuno-competence, which complicates the course of the main oncological disease, and sometimes, in the development of organ and systemic disorders, limits the possibilities for an adequate course of antitumor treatment [3, 1934; 6, -P. 541]. To increase the possibility of timely chemotherapy, great importance is attached to methods leading to a decrease in endogenous intoxication and an increase in the body's immunoreficiency. Such methods include plasmapheresis (PPh) and extra-corporeal immunopharmacotherapy (EIPHT) [1, -P.433; 2,-P. 169; 4, -P. 2246;8, -P.501]. The detoxification effect of plasmapheresis is not only the direct removal of toxins, biologically active substances and other various pathological substances from the bloodstream, as well as in an active drainage effect on the intercellular space and physiological detoxification systems that lead to enhanced toxin elimination mechanisms [9,-P. p. 23]. The main reasons for the ineffectiveness of efforts to improve long-term results of treatment of patients with ovarian cancer are the absence of
clear notions of etiology and pathogenesis, pathogno-monic symptoms of various stages of the disease, as well as low efficacy of treatment in stages III and IV and the absence of specific immunological methods of treatment [4, -P. 2246]. Recently, a lot of facts have accumulated, indicating the immunogenicity of various tumors, including cancer. To date, there is still no complete description of tumor-associated antigens expressed by tumor cells of the ovarian cancer, but even now they have identified: the protein cdr2 (associated with cerebellar degeneration); p53; HER-2 / neu; mes-otheliene; cancer-testicular antigens, etc. It has been established that the therapeutic approaches of antitumor immunotherapy are based on the stimulation of antitumor immunity as a result of action on the nonspecific or adaptive effector link of the immune system. It is recognized that the immune system recognizes the tumor process, forms specific antibodies and a pool of specific cytotoxic immunocompetent cells, which is an important condition for activation and implementation of antitumor immunity [1, -P.433; 4, -P. 2246; 6, P. 541; 7, -P.3399; 9, -P. 23]. However, up to now, data on the effectiveness of the use of immunotherapy in the combination of the treatment of patients with ovarian cancer have been lacking or insufficiently described in the literature [5, -P. 140; 6, -P. 541; 8,-P. 501; 10, -P. 1419]. At the same time, the severity and mechanisms of the development of immunodepression inherent in any oncological disease are different at different stages of tumor progression [8,-P. 501; 9, -P. 23]. In connection with what has been said above, ovarian cancer im-munotherapy is a relatively new direction used in medicine, and with high hopes [9, -P. 23;10, -P. 1419]. It should be noted that the great achievements in the field of molecular genetic studies stimulated a broad study of the possibilities of immunotherapeutic methods for the treatment of cancer patients. Therefore, the main purpose of this study is to study the degree of immuno-logical disorders in patients with OC, in particular, the basic parameters of congenital and adaptive immunity, as well as a certain spectrum of cytokines before the application of various types of immunotherapy and against the background of EIPHT and PPh.
Materials and methods of research. A total of 176 patients with stage T2-3N0-1M0 stages (II-III clinical stages) who were hospitalized in oncogynecology and chemotherapy departments of the RSCPMCOR MOH RUz from 2005 to 2012 were included in the survey. In accordance with the objectives of the study, the following groups of patients with OC were randomized to per-
form a comparative analysis of the immunological results depending on the immunotherapy method used, which was included in the complex treatment: group 1 - 28 practically healthy individuals; Group 2 - 36 patients with OC before treatment; Group 3 - 42 patients with OC who received immunotherapy in the form of extracorporeal immunopharmacotherapy (EIPHT); Group 4 - 44 patients with OC who received immuno-therapy in the form of extracorporeal immunopharma-cotherapy and plasmapheresis (EIPHT + PPh); Group 5 (control) - 54 patients with OC without immunother-apy. Clinical-laboratory and instrumental, morphological methods of investigation were conducted for all patients with OC.
Combined therapy in adjuvant or neoadjuvant regimen was carried out in patients with cancer, including polychemotherapy with the cisplatin regimen of 75 mg / m2 + cyclophosphamide 1000 mg / m2 for 1 day for 4-6 courses 1 time every 3 weeks and surgical treatment in the volume of a radical operation. Chemotherapy was performed in both adjuvant and neoadjuvant regimens. EIPHT and EIPHT + PPh in patients with OC using immunomodulators were carried out during the period of radiotherapy and chemotherapy in the hospital. The method of extracorporeal immunopharmacotherapy (EIPHT) was used to reduce toxic effects after chemotherapy and radiation therapy. Extracorporeal im-munopharmacotherapy was performed by exfusion of 500-1000 ml of autoblood in sterile containers "Gemakon" or "Terumo" and its centrifugation at 3000 rpm for 30 minutes. 50-80 ml of the supernatant of the blood plasma were removed. Then the obtained leukotrombo-mass and erythrocytic mass were incubated with an im-munotropic drug in a total dose of 30 mg at 37 ° C for 60-100 minutes, with the subsequent return of the conjugate to the circulatory system of patients [9, 9, -P. 23]. To stimulate the cellular immunity, an immunotropic drug, polyoxidonium, was used. Immunotherapy was performed in the hospital, when patients were admitted to chemotherapy and radiation therapy. In total, patients received 2 EIPHT sessions at the beginning of admission to hospital and before discharge from the hospital. As an immunomodulator, polyoxidonium (azoxime bromide) was used. Manufacturer - NPO PETROVAKS PHARM, LLC (Russia). Immunologi-cal studies included the study of cellular and humoral parameters of the immune system in patients with ovarian cancer. Determination of cellular immunity (CD3 +, CD3 + CD4 +, CD3 + CD8 +, CD95 +) was performed by flow cytometry on AccuriC6 (USA) using monoclonal antibodies. The humoral link of immunity was assessed by the determination of circulating immune complexes of small and large values in the serum of peripheral blood by the ELISA method. Immunological studies included a serum evaluation of the main cy-tokines of the immune system. Serum levels of cyto-kines (IL-6, TNF-a) were determined by ELISA using the test systems of the firm "Human" (Germany) in the dynamics of complex treatment. During the statistical analysis of the data presented in the work, the results of the research were entered into databases prepared in Microsoft Excel XP. Numerical (continuous) values were presented as mean arithmetic mean values and
mean error (M ± m). A comparison of the quantitative traits was carried out with the help of the Student's test, for continuous variables - the paired Student test. As a boundary comparative criterion for the statistical significance of reliability, p <0.05 was assumed.
The results of the research and their discussion. It is known that all malignant processes are recognized as secondary immunodeficiency states, accompanied mainly by immunodepression of the T-cell link of immunity [6, -P. 541;7,-P. 3399; 9,-P.23; 10,-P. 1419]. Therefore, the study of the state of immunoreactivity in patients with ovarian cancer is an important factor in determining the depth of immunodeficiency and predicting the disease. Moreover, the results obtained will make it possible to conduct more targeted immunother-apy. Despite a significant deepening in the last decade of ideas in the etiology, immunopathogenesis, progression and progression of malignant processes, many questions concerning the mechanisms of development of the pathological process and its course, assessing the effectiveness of treatment remain open. Proceeding from the foregoing, we set the goal to study the basic parameters of adaptive immunity and the main cyto-kines of the immune system.
The study of the relative content of the total pool of lymphocytes between the study groups of patients with ovarian cancer showed that the number of lymphocytes was significantly suppressed in all groups of patients compared to the value of a practically healthy group. When compared with patients after EIPHT + PPh, in whom there was a significant increase in the total number of lymphocytes after PCT. A significantly lower lymphocyte count was observed in patient groups before treatment and without immunotherapy in complex treatment. Thus, the level of lymphocytes in the group of patients without the use of immunotherapy was 29.5 ± 1.4%, whereas after EIPHT - 35.9 ± 1.39%, and with EIPHT + PPh - 42.2 ± 1.5%. The analysis showed that the use of any immunotherapy options (EIPHT, EIPHT + PPh) in the PCT complex can greatly improve the cellular indices of the immune system and bring them closer to the normative values. Next, we studied CD3 +, CD3 + CD4 +, CD3 + CD8 +, IRI.
Analysis of the immunophenotype CD3 + T-lym-phocytes in patients with ovarian cancer showed a significant suppression of CD3 + expression on T-lym-phocytes, which is observed in all groups of patients with OC compared with the control group (p <0.05). A significantly lower CD3 + T-lymphocyte count is observed in the group of patients with OC after PCT without immunotherapy. Significant suppression of CD3 + T-lymphocyte expression in the group of patients after PCT without immunotherapy is observed in comparison with the values of patients with OC in the groups where EIPHT and EIPHT + PPh were used. Thus, in the group of patients with OC after PCT without immu-notherapy, a decrease in CD3 + expression was detected, it has a toxic and depressive effect of PCT on factors of cellular immunity. Suppression of T-lympho-cytes (CD3 +) was mainly due to suppression of CD3 + CD4 + expression. The study of expression of CD3 + CD4 + on T-lymphocytes, which are the main regulatory cells of immunity, showed that the lowest value
was noted in groups of patients with OC without the use of immunotherapy and before treatment (p <0.05). The analysis showed that in the group of patients with OC without immunotherapy, the expression of CD3 + CD4 + was 21.6 ± 1.43%, while in the groups of patients after EIPHT - 27.2 ± 1.3%, after EIPHT + PPh - 29.5 ± 1,6%, and in the group of patients before the start of therapy - 20,4 ± 1,16%, in the group of practically healthy persons - 36,8 ± 1,2%.
CD3 + CD8 + T-lymphocytes play a major role in the implementation of antitumor immunity, which cause the death of tumor cells and their ability to secrete antitumor factors - cytokines [8,-P. 501;10, -P. 1419]. Analysis of the expression of CD3 + CD8 + on T-lym-phocytes revealed a significant increase in their values in all groups of patients with OC compared with the value of a group of practically healthy individuals. The maximum increase in CD3 + CD8 + was characteristic for patients with OC before treatment and after PCT without immunotherapy (p <0.05). When analyzing the CD3 + CD8 + values on T-lymphocytes between the study groups of patients, it is evident that before the treatment the expression of CD3 + CD8 + was significantly increased and amounted to 36.4 ± 1.88%, in the group of patients after PCT without immunotherapy was an average of 32, 8 ± 0.94%, and in the groups of patients after EIPHT and EIPHT + PPh a significant decrease in the number of cytotoxic T-lymphocytes and an approximation to the values of the control group was observed. This indicates an improvement in the state of adaptive immunity against the background of the use of various immunotherapy options with the use of polyox-idonium, which is a detoxification and immunomodu-lating drug. Immunoregulatory index (IRI), which is the ratio of CD3 + CD4 + / CD3 + CD8 + values, is of significant importance in secondary immunodeficiency states. It is known that, in healthy IRI, an average of 1.62 ± 0.02. Obviously, suppression of CD3 + CD4 + expression against the background of increased expression of CD3 + CD8 + leads to a decrease in IRI. It was revealed that the reduced value of IRI was noted in the group of patients before and after treatment without im-munotherapy. Patients with ovarian cancer who underwent EIPHT after PCT had a reduced IRI compared to those who received EIPHT + PPh. Thus, the lowest value of IRI in the group of patients after PCT without immunotherapy was 0.69 ± 0.02, and the highest value was noted in the group of patients after EIPHT + PPh and amounted to 1.44 ± 0.02 (p <0.05 ). It follows that the expressed immunosuppression was characteristic of patients with OC in the groups of patients prior to treatment and after PCT without immunotherapy. Apparently, the decrease in IRI is an important criterion for the depth of the T-cell immunodeficiency state, especially when assessing the effectiveness of treatment for ovarian cancer. Next, the most famous but interesting activation marker of lymphocytes was studied. From the available literature data it is known that analysis of activation lymphocyte markers allows studying the processes of activation, proliferation, differentiation and apoptosis of immunocompetent cells and characterizes the associated cell cycles associated with these processes [6, -P. 541; 7, -P.3399; 9,-P.23]. So, we studied
the marker of lymphocytes CD95 +. According to the literature, the APO-1 / Fas (CD95 +) receptor is a reflection of the level of apoptosis of lymphocytes [3,6]. It was found that the growth of expression of CD95 + receptors on lymphocytes indicates an excessive and ineffective process of stimulation of blood lymphocytes, which indicates an apoptotic pathway of lymphocyte death [5, -P. 140; 8, -P.501]. The analysis showed that in the groups of patients with OC there is an increased expression of CD95 +. Moreover, the greatest expression is observed in groups of patients before and after PCT therapy without immunotherapy. Normal values of CD95 + expression are observed in groups of patients after PCT with EIPHT and EIPHT + PPh, which is associated with the effect of polyoxidonium on lymphocyte receptors and the provision of immuno-tropic action.
Increased expression of the marker of apoptosis of lymphocytes is a characteristic sign of malignant processes, which explains the depletion of the pool of lymphocytes and the formation of an immunodeficiency state. Obviously, excessive apoptosis promotes the formation of deep T-cell immunodeficiency, which contributes to the progression of the disease. Thus, pronounced changes in the cell link of immunity were revealed, which are manifested by suppression of CD3 +, CD3 + CD4 +, IRI expression and increased expression of CD3 + CD8 +, CD95 + on T-lymphocytes. One of the important humoral markers of immunity is the circulating immune complexes (CIC) of small and large sizes. It has been established that they possess the most important biological functions, which consist in binding the antibody to the antigen, and the formation of the CIC. It is known that an important characteristic of the CIC is their magnitude, which can be large and small. The analysis showed that the CIC of large and small sizes in all groups of patients with ovarian cancer were significantly increased. Thus, the CIC of large quantities were significantly increased before and after PCT therapy without immunotherapy. In the groups of patients after EIPHT and EIPHT + PPh, the CIC of large values significantly decreased, which indicates the detoxification effect after PPh and the use of polyoxido-nium. The CIC of small values was significantly increased in groups of patients with OC before and after PCT therapy without immunotherapy. Obviously, this is due to the lack of the necessary detoxification and the unrealized monocyte-macrophage system. It is known that the CIC3% of large quantities formed with an excess of antibodies, although able to bind complement, but are large in size, are insoluble, so they are rapidly phagocytosed and have low pathogenicity. The greatest pathological potential is possessed by soluble CICs of 4%, which were formed with an excess of antigen [4, -P. 2246; 6, P. 541; 8, -P.501;9,-P.23]. Consequently, a high level of CIC of both values for OC may be due to suppression of the mechanisms of elimination and phagocytosis, which in turn is due to the suppression of the innate immunity function [4, -P. 2246; 7, -P. 3399]. Thus, the activation of humoral immunity is observed due to the increased values of the CIC of both values along with the pronounced depression of the adaptive
cellular immunity. In turn, adaptive immunity is characterized by an imbalance in the cell link of immunity, which is expressed in the suppression of a common pool of lymphocytes, a common pool of T lymphocytes, IRI due to a decrease in the number of T helper / inducers and an increase in T-cytotoxic lymphocytes. CICs of large and small values were also increased, however, the highest increase in CIC was observed in patient groups before PCT and immunotherapy, and after application of PCTs without accompanying immunotherapy. Obviously, with this pathology T - the cellular immune response is significantly weakened, which suggests clonal depletion of T lymphocytes. In turn, the reduced immunoreactivity of the T-cell link can be considered as a result of a disruption of the tumor antigen presentation to cells of the immune system, as well as a disruption of the function of the T cells themselves. Activation of CD95 + on T-lymphocytes confirms the presence of T-cell immunodeficiency due to death or apoptosis of T-lymphocytes. The increase of these markers always indicates the depth of immunodeficiency, which aggravates the pathological process. A 4% increase in the CIC is a marker of progression and deterioration of the clinical course of the disease. The
study of the adaptive link of immunity against the background of immunotherapy established the positive clinical effectiveness of the accompanying immunotherapy against PCT. According to the literature, IL-6 is a key pro-inflammatory cytokine, an important role of which belongs to the development of the inflammatory process and stimulation of the production of other cytokines. Simultaneously, IL-6 plays an important role in cancer processes [1]. It is known that proinflammatory cytokines, in particular, IL-6 and TNF-a, have a systemic effect [7,-P. 3399]. In turn, the result of systemic action on the body of proinflammatory cytokines is the development of immunodeficiency state [3,5,7,9,]. The study of the state of the mediators of the immune system in malignant processes undergoes certain difficulties, which are expressed in the instability of the oncological process, in the presence of various forms and morphological variants of the disease. In this regard, the study of cytokines in patients with ovarian cancer has not only scientific but also practical value for assessing the depth of immunodeficiency and predicting the disease. The analysis of the main cytokines of the immune system is presented in Table 1.
Table 1. The main cytokines of the immune system in patients with ovarian cancer on the background of immunotherapy_
Indicators Healthy. group ( gr.1) The group before PCT (gr.2) The group after PCT without IT (gr. 3.) The group . after PCT on the EIPHT background The group after PCT on the EIPHT+PPh background (gr. 5 )
IL-6 6,5±0,45 48,9±2,9* 64,8±2,6*A 31,9±3,6*A# 15,8±1,25*A#@
TNF-a 4,5+0,8 24,8±1,2* 38,9±1,77*A 22,4±1,19*# 16,2±1,9*A#@
Note: * - reliability of differences in groups compared to the 1st group; A - reliability of differences compared to the 2nd group; # - reliability of differences compared to the 3rd gr.; @ - reliability of the differences compared to the 4th group. (p <0.05)
The study of IL-6 revealed a statistically significant increase in all groups of patients with ovarian cancer compared with group 1 of healthy individuals. Analysis of the studies showed that IL-6 values were statistically increased in all groups of patients when comparing them with each other. A comparative analysis of IL-6 levels between groups revealed that when compared with group 1, the level of IL-6 was increased in the 2nd group of patients to PCT 7.6 times, in the 3rd group after PCT without immunotherapy - in 9 , 6 times, in the 4th group after PCT in the EIPHT complex - 4.8 times and in the 5th group of patients after PCT in the complex EIPHT + PPh - 2.7 times. Evidently, the highest level of IL-6 in the serum of peripheral blood was detected in the group of patients after PCT without IT. It was shown that, after PCT without IT, increased values of IL-6 are observed. It is known that IL-6 is an important diagnostic index of malignancy of the oncological process. It is known that high levels of IL-6 may interfere with effective immunotherapy [10, -P. 1419]. IL-6 is a pleiotropic cytokine with a wide range of biological activity, which is produced by both lymphoid and non-lymphoid cells of the organism [6, -P. 541; 9,-P. 23]. Thus, the EIPHT and EIPHT + PPh in PCT com-
plex in patients with OC with the presence of tumor intoxication causes a positive dynamics of the main parameters of the immune system, as well as a decrease in the level of serum pro-inflammatory cytokines, some of which have a growth-stimulating effect, for example, IL-6.
Further, the level of TNF-a was studied, which according to literature is an immunological marker of malignancy and progression of the oncological process [4, P. 2246; 6, P. 541; 8, -P.501; 10, -P. 1419]. The TNF-a analysis showed a significant increase in its values in all study groups of patients with OC compared with the 1 st group of healthy individuals. The only exception was the absence of a significant difference in the content of TNF-a between the 2 nd and 4 th groups of patients with OC. Comparative analysis of TNF-a levels with the 1 st group of healthy individuals showed that the level of TNF-a was increased in the 2 nd group of patients to PCT in 5.64 times, in the third group after PCT without IT - in 7.8 times, in the 4th group after PCT in the complex EIPHT - 4.5 times and in the 5 th group of patients after PCT in the complex EIPHT + PPh - 3.7 times. It can be seen that the highest level of TNF-a in the serum of peripheral blood was detected in the third group of patients after PCT without IT. It was shown
that by the end of treatment in the 5 th group of patients there was a significant decrease in the level of TNF-a, which was associated with an improvement in the overall condition of patients. Consequently, the level of TNF-a correlates with the clinical data of the disease and depends on the degree of effectiveness of therapy. Thus, an increase in proinflammatory cytokines in the blood serum of patients with ovarian cancer was detected, which was characterized by an increased content of IL-6, which can also be attributed to anti-inflammatory cytokines. Inclusion in the complex of accompanying treatment of EIPHT and EIPHT + PPh, is one of the ways to reduce endogenous intoxication during antitumor drug therapy. Application of the abovemen-tioned immunotherapy methods, according to modern literature, can serve as a modifier of chemotherapeutic treatment, since its tolerance directly depends on the functional state of the organs and systems of physiological detoxification of the organism [7,-P. 3399], and also on the functional activity of the immune system. The conducted studies showed that immunotherapy regimens, including the use of EIPHT and EIPHT + PPh, have the greatest effectiveness in reducing the side effects of PCT in the complex treatment of patients with stage II-III stage II, as well as in improving the subjective state of patients and their quality of life.
Clinically, the main clinical manifestations of toxicity of PCT, improvement of the subjective state of the patient and the basic laboratory parameters of peripheral blood are reduced. The developed EIPHT technique has great prospects in oncological practice in connection with the possibility to remove the consequences of cancer and chemoradiation intoxication, and also to activate the system of antitumor protection of the body, which should positively affect the outcome of the disease and lead to an increase in the quality and life span of the patient. The use of EIPHT and EIPHT + PPh with subsequent neoadjuvant PCT in patients with ovarian cancer with clinico-laboratory signs of endogenous intoxication is a justified and effective method, since it leads to normalization of the indices of the main serum cytokines of the immune system, allows to improve immediate results of treatment, leads to a reduction in clinical manifestations of the disease , improves the quality of life of patients, allows you to transfer patients from an inoperable state to an operable state. Moreover, it can be seen that in addition to the detoxification effect, immunotherapy also has immunomodu-latory actions, especially with the use of immunomod-ulating drugs. The dynamics to the normalization of the phagocytic level and the content of immunoregulatory cytokines was also revealed.
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Information about the main author:
33. Kamishov Sergey Viktorovich
34. MD, PhD, chemotherapeutist of chemotherapy department
35. Senior researcher
36. ID: ORCID 0000-0002-1581-6032
37. Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology of the Ministry of Health of the Republic of Uzbekistan, Tashkent, Uzbekistan
38. 100174, Uzbekistan, Tashkent, 383 Farabiy
st.
39. +998 90 978 65 38
40. E-mail: sergei_kamyshov@mail.ru
